Chantix: 36,342 adverse events, 595 suicide attempts

Chantix: 36,342 adverse events, 595 suicide attempts

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May 22 08 5:08 AM

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Strong Safety Signal Seen for New Varenicline Risks

May 21, 2008

EXECUTIVE SUMMARY

A strong signal of multiple safety problems with Chantix (varenicline), a drug to help people stop smoking, has been seen in a pilot program to identify new drug risks in adverse drug events reported to the U.S. Food and Drug Administration.

Varenicline is suspected in various adverse drug event reports of causing a wide spectrum of injuries, including serious accidents and falls, potentially lethal cardiac rhythm disturbances, severe skin reactions, acute myocardial infarction, seizures, diabetes, psychosis, aggression and suicide. The cases were analyzed and classified using computerized excerpts of adverse event reports which the FDA publishes for research use.

The FDA approved varenicline in May 2006 after granting it a priority review. Varenicline is a partial agonist of one of the nicotinic acetylcholine receptors in the brain and nervous system,1 and currently the only marketed and approved drug with this mechanism of action.

In the 4th quarter of 2007 varenicline accounted for 988 serious injuries in the U.S. reported to the FDA, more than any other individual drug in this time period. By comparison the FDA received a median of 5 reports of serious injury for 769 different drugs in the 4th quarter. Only 35 drugs accounted for 100 or more reports. This large volume of reports prompted us to conduct an analysis of all adverse events for varenicline since marketing approval in 2006.

The FDA has recently issued a Public Health Advisory about one of the most marked adverse effects of varenicline, psychiatric symptoms that included "changes in behavior, agitation, suicidal ideation, attempted and completed suicide." 2 However, the FDA alert provided no information about the numbers of reported neuropsychiatric events among treated smokers.

From May 2006 through December 2007, the FDA had received 227 domestic reports of suicidal acts, thoughts or behaviors, 397 cases of possible psychosis and 525 reports of hostility or aggression. These totals included 28 cases of suicide and 41 mentions of homicidal ideation, 60 cases of paranoia and 55 cases of hallucination. The categories were not mutually exclusive.

However, the adverse drug event reports for varenicline describe other kinds of serious harm for which no warnings now exist, either from the FDA or from the manufacturer, Pfizer Inc. The cases (including those with psychiatric effects) were classified using standardized medical queries developed by the pharmaceutical industry to identify potential adverse events in clinical studies and postmarket surveillance. Adverse event reports in themselves do not establish a causal link to the drug, only that an observer suspected a relationship. Depending on the features of the specific event, it could be counted in multiple categories, and classifications are not definitive. Among the most prominent were:

Accidents and injuries. A total of 173 serious events described accidental injury, including 28 road traffic accidents and 77 falls, some leading to fractures of rib, facial bones, hand, ankle, spine, and lower limbs. In these cases a variety of potential causes were identified, including loss of consciousness, mental confusion, dizziness and muscle spasms.

Vision disturbance. At least 148 reports contained medical terms indicating vision disturbances, including 68 cases described as blurred vision and 26 terms indicating transient or other forms of blindness. This reported effect could also describe a mechanism that could or did contribute to accidents and injuries.

Heart rhythm disturbances. The FDA received 224 domestic reports classified as potential cardiac rhythm disturbances. This category, however, was dominated by reports of sudden loss of consciousness, an event that could also have non-cardiac causes. However, this category also included smaller numbers of cardiac arrests and identifiable abnormal cardiac rhythms

Seizures and abnormal muscle spasms or movements. Serious reported events included 86 cases of convulsions (seizures), 372 reports of a wide variety of movement disorders, including tremors, muscle spasms, twitching, tics, drooling, and motor hyperactivity. The extent to which these problems resolved with a reduced dose or by halting treatment could not be determined from these data.

Moderate and severe skin reactions. Reported serious events included 338 cases of hives or swelling of the tongue, face, eyes, lips or other areas. In addition, 65 cases were classified as severe and included blisters, exfoliation of the skin and lips, and Stevens-Johnson Syndrome.

Diabetes. The FDA has received 544 reports suggesting varenicline may be related to a loss of glycemic control. This category included many cases of weight loss or gain that could have alternative causes, but also identified numerous cases of symptoms and laboratory tests consistent with new onset diabetes.

Recommendations

We have immediate safety concerns about the use of varenicline among persons operating aircraft, trains, buses and other vehicles, or in other settings where a lapse in alertness or motor control could lead to massive, serious injury. Other examples include persons operating nuclear power reactors, high-rise construction cranes or life-sustaining medical devices. Based on reports of sudden loss of consciousness, seizures, muscle spasms, vision disturbances, hallucinations, paranoia and psychosis, we believe varenicline may not be safe to use in these settings. The extent to which varenicline has already contributed to accidental death and injury has not yet been investigated because these adverse effects had not been previously reported. The Federal Aviation Administration approved varenicline for use by airline pilots3 before most of these reports were available.

In addition, we recommend that patients and doctors exercise caution in the use of varenicline and consider the use of alternative approaches to smoking cessation.

Finally, we urge the FDA and the manufacturer to provide warnings to doctors and patients for those adverse effects that can be adequately documented through existing data, and to undertake on a priority basis epidemiological studies or other research to assess other potential risks. We promptly notified the FDA of our findings.

This report was written by:

Thomas J. Moore, Senior Scientist, Drug Safety and Policy, ISMP

Michael R. Cohen RPh, MS, ScD, President, ISMP

Curt D. Furberg, MD, PhD, Professor of Public Health Sciences, Wake Forest University School of Medicine.

Chantix blamed for 3,063
serious injuries and 78 deaths

May 21, 2008

A study released today examined 6,363 U.S. Food and Drug Administration (FDA)
adverse drug reaction reports implicating Pfizer's quit smoking pill Chantix
(varenicline) and found that 3,063 involved serious injuries. Its recommendation? "We recommend that patients and doctors exercise caution in the use
of varenicline and consider the use of alternative approaches to smoking cessation."

Authored by The Institute for Safe Medication Practices (ISMP), a non-profit medication watchdog, ISMP looks for safety flags while monitoring all
adverse events reported to the FDA for all medications.

ISMP monitoring noted that "by the 3rd quarter of 2007 varenicline produced a signal not previously seen for any other drug. It produced more
serious reports than any other drug for multiple types of events: more potential cases of angioedema, cardiac arrhythmia, diabetes and severe cutaneous
injury. By the 4th quarter of 2007 varenicline accounted for more reports of serious drug adverse events in the United States than any other
drug."

During the 4th quarter of 2007 the FDA received 998 reports of serious varenicline adverse events compared to only 372 for the addictive
troublemaker oxycodone, a potent medication for relief of moderate to severe pain. While ISMP estimates that a total of 3.5 million Chantix (varenicline)
prescriptions were written in the U.S. since FDA approval in May 2006, government estimates place annual oxycodone prescriptions written at more than 7
million.

The study found that while the FDA has issued warnings regarding Chantix's link to suicidal acts, thoughts or behaviors, psychosis, hostility and
aggression, it has ignored "other kinds of serious harm for which no warnings now exist, either from the FDA or from the manufacturer, Pfizer
Inc."

While the FDA received 78 death reports in which "varenicline was the principal suspect drug," only 28 resulted from suicide. There were
"numerous reports suggesting cardiac causes, both thromboembolic and arrhythmic," writes ISMP.

Could there possibly be a common thread among such a diverse group of disorders? Yes, says the ISMP study. A subtype of acetylcholine receptor known as
alpha 4 beta 2 plays "numerous roles in the brain and body and is central to muscle contractions -- both voluntary movement and heart muscle
contractions, as well as the tone of the smooth muscles that line the blood vessels."

According to the study, Pfizer researchers found that varenicline was most active against alpha 4 beta 2 type acetylcholine receptors. They focused on
the fact that it caused the release of dopamine within the brain while blocking nicotine from occupying alpha 4 beta 2 receptors. It notes that "many
antipsychotic drugs block dopamine receptors, but they also cause movement disorders. The loss of muscle control seen in Parkinson's disease is the
result of the destruction of dopamine-producing cells in the brain."

The gravity and number of serious injuries attributed to Chantix caused the report to lightly touch on an equally pressing risk analysis concern, the
value of Chantix in helping smokers quit. While noting that counseling rich varenicline clinical trials produced 52-week quit rates of approximately 22
percent, it cites two early nicotine gum studies while noting that they achieved comparable rates.

In fact, a 1976 nicotine gum study headed by Russell found that 23% of nicotine gum users were still not smoking at 1 year. The 1980 nicotine gum study
by Raw produced a whopping 38% rate, in 1982 Jarvis found a 31% rate, in 1983 Schneider 30%, in 1984 Hialmarson 29%, in 1986 Daughton 31%, in 1987
Kornitzer 32%, and in 1989 Tonnesen boasted a 44% one year quit smoking rate.

What wasn't mentioned in the ISMP study was that in real-world competition, outside of clinical trials that were rich in support and counseling,
nearly all quitting method surveys to date show that, long-term, cold turkey quitters actually perform better than users of nicotine gum, patch, lozenge
and Zyban.

A 2006 National Cancer Institute quitting method survey of 8,200 smokers found that at 9 months 16% of "on your own" quitters were still not
smoking compared to just 14% among quitters relying upon the nicotine patch, gum, lozenge or Zyban.

While ISMP faults the FDA for neglect in warning Chantix users about risks other than mental and emotional, just as culpable is its approval of
Pfizer's clinical trial design when: (1) they involved a record number of provider counseling/support contacts (twenty-five), contacts the FDA knows
could account for nearly all effectiveness seen; (2) no assessments to test study blinding was requested or conducted, when the FDA knows that it is
probably impossible to blind drug addiction studies, as smokers with any quitting history recognize the onset of full-blown nicotine withdrawal; (3)
excluded 28% of study applicants, including nearly all having any significant medical condition, and then permitted Pfizer to market Chantix to groups
intentionally excluded; and (4) allowed NRT use between the end of treatment and week 52, and then certified ongoing NRT users as having been successful
Chantix quitters.

If Pfizer knows, via real-world quitting data gathered through its www.GetQuit.com website, that
Chantix's real-world effectiveness is substantially less than shown in clinical trials, with Chantix injuries so numerous and serious, does Pfizer have
both legal and ethical duties to immediately share that data with both the FDA and smokers considering using Chantix?

If Chantix isn't living up to Pfizer marketing hype, do reports like this ISMP study obligate Pfizer to be more forthright, honest and clear about
both varenicline's safety and effectiveness?

"These data provide a strong signal that the risks of varenicline treatment have been underestimated, and show that a wide spectrum of serious
injuries are being reported in large numbers," ISMP warns.

"Table 1 shows that in the 4th quarter of 2007, the other highest ranked drugs (e.g. fentanyl, interferon beta, etanercept) are all high alert
drugs with black box warnings, are intended for serious illness in patients and have benefits that are accompanied by substantial risks. In comparison,
varenicline is intended for use in healthy people to help stop smoking."

Does it make sense, if inside a very slow burning building, to pay money for the right to use the most dangerous exist path out?

Never in the history of smoking cessation has any quitting product harmed so many. It makes one wonder whether instead of helping smokers the FDA and
Pfizer have declared war upon them.

XXX

No Copyright - This Article is Public Domain

John R. Polito is solely responsible for the content of this article.
Any factual error will be immediately corrected upon receipt of credible authority
in support of the writer's contention. E-mail comments to john@whyquit.com

F.A.A. Bans Antismoking Drug, Citing Side Effects

By STEPHANIE SAUL

The Federal Aviation Administration said Wednesday it would no longer permit pilots or air traffic controllers to use the smoking cessation drug
Chantix, citing potential side effects that could pose a threat to the safe operation of aircraft.

The Food and Drug Administration issued a public
health advisory in February, saying that some Chantix users had developed a variety of serious psychiatric symptoms, and that some had committed
suicide.

An F.A.A. spokeswoman, Laura Brown, said the
agency had approved the use of Chantix for airline pilots and flight controllers last year, but was notifying 150 pilots and 30 air traffic controllers
known to be using it that the drug was no longer acceptable and should be discontinued.

Ms. Brown said the decision was based on emerging data on the drug, including a report from a watchdog group, the Institute for Safe Medication
Practices, linking Chantix to a wide array of health and safety problems. They include accidents and falls, potentially lethal heart rhythm disturbances,
heart attacks, seizures, diabetes and various psychiatric disturbances.

The institute's findings, which were based on an analysis of adverse events reported to the F.D.A., said that from May 2006 through December 2007,
there were 227 reports of suicide attempts or suicides, 397 cases of possible psychosis and 525 reports of hostility or aggression. Those reports included
28 suicides and 41 mentions of homicidal thoughts, 60 cases of paranoia and 55 cases of hallucinations.

The data, the report said, "provide a strong signal" that the risks of treatment with varenicline, the active chemical in Chantix, have been
underestimated. This year, Public Citizen's Health Research Group, another consumer watchdog organization, had called for a black-box warning -
F.D.A.'s strongest drug alert - on Chantix.

Chantix, made by Pfizer, was approved in 2006 for sale in this country and the European Union. Worldwide sales of the drug were $883 million last
year, and an estimated 6.5 million people have used it.

Pfizer issued a statement Wednesday saying that the current labeling for Chantix reflected the product's safety profile, including warnings that it
had the potential to cause psychiatric problems and might impair driving.

"There are few things that provide greater health benefits than quitting smoking," said the Pfizer statement, issued by a company spokesman,
Francisco Gebauer. "When considering the use of Chantix for their patients, health care providers should discuss the risks of smoking, the health
benefits of quitting smoking, and the product's efficacy and safety profile."

Chantix, taken in pill form, partly blocks and partly stimulates a nicotine receptor in the brain and in clinical studies was shown to help smokers
quit. Potential problems associated with Chantix were first publicized last September when a Dallas musician, Jeffrey Carter Albrecht, was shot to death
after he began behaving bizarrely while taking Chantix.

The Institute for Safe Medication Practices study noted that some of the reports of adverse events it analyzed could have been spurred by that publicity
and by a November 2007 early warning about the drug from the F.D.A.

An F.D.A. spokeswoman, Susan Cruzan, said the agency was also conducting a special safety review of Chantix and was requiring pharmacists to distribute
a medication guide to patients, warning of the potential side effects.

The F.A.A. was also planning to notify associations representing both commercial and private pilots that Chantix was no longer permitted, Ms. Brown
said.

Good for the FAA! They are protecting their employees, even if they are probably just trying to avoid a law suit due to the possibility of planes crashing
when managed by people on Chantix...

This whole Chantix affair is scandalous. Even if the FDA will now distribute a "medication guide" that warns patients of the side effects of
Chantix, the prescription itslef is construed by patients as a medical endorsement of the product...

We ask members to remain mindful that here inside Freedom our mission truly is single minded: nicotine cessation. Whether your family is into tobacco
farming or you are an executive at a tobacco company or work for Pfizer or are a health care provider who has recommended Chantix or Champix, you are as
welcome here as any. This forum cannot permit posts that attack or vilify any profession or occupation or that have potential to promote debate that
could divide or weaken the forum's support efforts and damage its mission.

Chantix is once again being actively marketed by Pfizer here in the U.S. and it won't be long before it's back in the headlines. So far, 5 of
6 varenicline sales worldwide have been in the United States. I'm told that reports of serious adverse reactions continue to pour into the FDA.
Product liability lawsuits are now being filed across the nation on behalf of hundreds of users who have committed or attempted suicide, or sustained
other serious injury or death.

Over the next two years Pfizer will be compelled to produce risk-benefit documentation showing what it knew both in regard to risks and effectiveness
and when it knew it. This is the first time ever that nationwide civil litigation has focused upon a cessation product. We can expect lots of
finger-pointing and headlines.

We will continue to share risk and effectiveness news here at Freedom for the the benefit of visitors looking in who may be considering varenicline.
We may even share judicial findings. What we will not do is share allegations and arguments that will be traded during litigation, or permit attack upon
any lawful occupation. There are plenty of forums that invite such discussions. If our objective is operation of a forum where all who are dependent upon
nicotine are made to feel comfortable being here then this cannot be one of them.

Our sincere thanks to all members for helping keep Freedom united, strong and focused upon the forum's mission, staying nicotine-free today.

Pfizer's Chantix
Continues Killing Quitters

October 22, 2008

Marketed
in the U.S. as Chantix and other nations as Champix, another bomb just fell on Pfizer's quit smoking pill varenicline. According to a just released
report by The Institute for Safe Medication Practices (ISMP), a non-profit medication watchdog, "In the first quarter of 2008, varenicline accounted
for more reports of serious injury than the 10 best selling brand name prescription drugs combined."

The report indicates that the U.S. Food and Drug Administration (FDA) received serious adverse event reports on 773 different drugs during the 1st
quarter of 2008. Chantix topped the list. During that period there were 1,001 new reports of serious injuries among varenicline users, including 50
additional deaths. By comparison, varenicline users accounted for 998 serious injury reports and 78 deaths during the 4th quarter of 2007.

The ISMP report notes that there were only 17 reports of serious injury among all forms of nicotine replacement therapy combined (the nicotine patch,
gum, lozenge, spray, and inhaler). This quitting method risk data, when combined with results from the only head-to-head study pitting varenicline against
NRT, should allow FDA officials to engaged in informed risk-benefit analysis.

A Pfizer smoking cessation study published in February 2008 compared 10
weeks of nicotine patch use to 12 weeks of varenicline use. Even after Pfizer gifted varenicline a two-week treatment advantage, varenicline failed to
prove superior in 7-day point prevalence findings. Participants were asked at both 6 months and 1 year whether or not they had smoked a cigarette in the
past 7 days. Pfizer's researchers, which included four Pfizer employees, were forced to report that there "were no significant differences"
between nicotine patch and Chantix smoking abstinence rates at either 6 months or a year.

According to the ISMP report, varenicline again recorded the highest number of suicide/self-harm events of any medication with 226. The combined total
for the next two closest drugs reporting suicide attempts was 22% less (oxycodone with 89 reports and acetaminophen with 87).

The ISMP report asserts that broader warnings are needed. It encourages the FDA and Pfizer to add a prominent warning about accident risks to both the
patient Medication Guide and prescribing information sheet for doctors, a warning similar to the new warnings about psychiatric side effects.

The ISMP report also flags additional kinds of side effects, including serious accidental injuries. It highlights traffic accidents and concerns that
varenicline induced seizures, disturbances in vision, panic attacks or impaired judgment may be playing a role.

It encourages further investigation of possible varenicline links to diabetes, potentially life-threatening interruption of the heart rhythm, heart
attacks, strokes, and moderate to severe allergic reactions.

The ISMP's May 2008 report raised concerns about potential alertness and motor control related accidents among transportation industry workers using
varenicline. In response, the Federal Aviation Administration banned the use of Chantix by airline pilots, the Department of Transportation limited its use
among truck drivers, and the Department of Defense prohibited its use by aircraft and missile crews.

This time the bomb dropped on varenicline may prove fatal. If varenicline is not more effective than NRT, while causing nearly 5,800% greater harm than
NRT, then why is it sill on the market? If the FDA has difficulty answering this question, it may well be that our nation's medication system has far
greater concerns than just varenicline.

As shown by the below articles, today the U.S. Food & Drug Administration (FDA) required that both Chantix, whose chemical name is varenicline and
that's marketed outside the US as Champix, and Zyban (bupropion) to carry the highest warning of all, a "Black Box," warning users of the risk of
suicide among other serious risks.

In addition to being used in smoking cessation, buproprion is also marketed as an atypical antidepressant under the brand name Wellbutrin, as well as in a
generic form. All these products will receive increased warnings highlighting the risks for mental health events. (The drugs already carry black box warnings
for suicidality.)

According to FDA, symptoms have occurred in patients with and without histories of psychiatric illness, and tend to occur shortly after medication starts and
end when treatment is stopped. But there have been instances reported where side effects continue even after the patient stops taking the drug.

According to raw FDA numbers, 98 people taking Pfizer's Chantix committed suicide, while 14 people took their lives while on GlaxoSmithKline's Zyban.
One hundred eighty-eight people attempted suicide on Chantix, and 17 tried while taking Zyban.

"It has been difficult to evaluate some of these cases, as we are working off adverse event reports," said Bob Rappaport, director, Division of
Anesthesia, Analgesia and Rheumatology Products, CDER. "People who stopped smoking without using medication may also report similar symptoms in nicotine
withdrawal. However, we examined some cases where people were using the products under discussion and also had the adverse events while smoking."
Rappaport admitted in a teleconference that both smoking cessation aids are effective, and possible risks should be weighed against the health benefits of
quitting smoking.

Both companies can continue to advertise the drugs, but additional warnings must be added to the risk statements. However, they will no longer be allowed to
run reminder ads.

About Time or Too Late?

Chantix came under fire last year in the blogosphere and media as hundreds of consumers began posting on Web forums that they had become increasingly depressed
while on the smoking cessation drug.

Minutes after FDA announced the call for increased warnings, Pfizer released a statement saying that it would update its labeling to add the black box warning
and adjust the current warning. Pfizer wouldn't comment whether recent public scrutiny has affected sales, or whether the company will retool its sales
force in light of the new warnings.

Zyban, Really?

The black box for Zyban, however, is a bit of a surprise.

"We looked at three products [including nicotine replacement treatments] to get some sort of idea if Chantix would stick out," Rappaport said.
"We were surprised to find that Zyban seemed out to have the same characteristic of [adverse] reporting and the same reporting rates. So this is a new
thing for Zyban."

Pfizer and GSK are being required to conduct clinical trials to determine incidents of mental health symptoms in people trying to quit smoking, including
people with and without pre-existing mental conditions.
FDA said that it doesn't expect the results of the trials to be revealed for several years.

Thomas J Moore AB, Joseph Glenmullen MD,Curt D Furberg MD PhD

BACKGROUND: Thoughts and acts of aggression/violencetoward others have been reported in postmarketing surveillanceof varenicline, an aid to smoking cessation.

OBJECTIVE: To identify the common characteristics of these thoughtsand acts of aggression/violence toward others and assess thelikely relationship to varenicline treatment.

METHODS: We obtained 78 adverse event reports from the Foodand Drug Administration MedWatch database containing medicalterms describing possible acts or thoughts of aggression/violence;4 additional cases were reported in clinical trials, and 3 otherscame from the published literature. We used psychiatric diagnosticcriteria and an adverse event causality assessment tool to identify26 case reports for study.

RESULTS: The selected casesdescribed 10 events with assault, 9 cases of homicidal ideation,and 7 cases of other thoughts or acts of aggression/violence.The most frequent common characteristics were (1) inexplicableand unprovoked event, (2) the victim was anyone nearby, (3)no indication of a prior history of similar behavior in thepatient, and (4) early onset of psychiatric adverse effects, oftenbefore stopping smoking. Where dechallenge/rechallenge informationwas available, psychiatric adverse effects resolved in 13/14(93%) cases after discontinuation.

CONCLUSIONS: Theclear temporal relationship, lack of prior history of this behavior, andunusual nature of these events strengthens the accumulatingscientific evidence that varenicline is associated with thoughtsand acts of aggression/violence. We recommend that physiciansand pharmacists ensure that all patients are informed of possiblepsychiatric symptoms of varenicline, including violent and aggressivethoughts. All patients should be advised to contact a health-careprovider immediately if these symptoms occur and vareniclineshould be discontinued without delay.

With Pfizer, FDA Shunning Tests on Mentally Ill, Promise of Smoking Remedy Chantix Turns to Ashes for Some

By Lilly Fowler on December 15, 2010

[omitted photo of: "Linda Ware with her granddaughter, two days before she committed suicide in 2008."]

Late one morning in June 2008, 57-year-old Southern California real estate agent Linda Ware was driving with her cousin along a desert highway when she began hallucinating. Envisioning in the distance a sign that read “God Is in the Realm,” she pulled over suddenly and ordered her cousin out of the car. Then, just as abruptly, Ware burst out laughing and pulled back onto the road again.

Although Ware suffered from depression, as her daughter Cary Ussery related, she’d never acted like this. A few days earlier, however, she had started taking Chantix, a pill meant to help her quit smoking by suppressing the effects of nicotine on the brain.

The day after the driving incident, a family friend found Linda Ware slumped by her bed, dead from a fatal cocktail of prescription drugs, a suicide note at her side.

Tragedy has plagued Chantix ever since it was approved in May, 2006, even as the drug has helped some smokers kick the habit. By mid-2009, the U.S. Food and Drug Administration had received reports of nearly 100 suicides, 200 attempted suicides and close to 5,000 serious psychiatric events overall. Hundreds of reports of side effects have continued to stream in this year.

A review of the drug’s history shows that Pfizer Inc., the giant pharmaceutical company that makes Chantix, failed in its years of clinical trials to test the product on the mentally ill or those with a recent history of depression — even though millions of smokers suffer from psychiatric problems. Moreover, FDA regulators approved Chantix after a speeded-up “priority review” process, and did not request a follow-up study on mentally ill patients using the medication, even though the agency’s own safety reviewer reported that the exclusion of such smokers may have undermined the clinical trials.

It wasn’t until three years later, after thousands of reports of serious side effects, that the FDA told Pfizer to conduct trials including people with a history of mental illness. The agency then also slapped a so-called black box warning, the FDA’s strongest alert, on the medication.

The controversy over Chantix’s side effects, particularly for smokers with mental health issues, has triggered a torrent of lawsuits. About 1,000 such cases have been filed in federal court, and plaintiffs lawyers say they anticipate bringing forward more than 1,000 additional suits. There also are scattered cases in state courts in New York, Illinois and elsewhere. Plaintiffs in more than half of the cases claim the drug led to suicides or suicide attempts, and many say they suffered psychosis, blackouts, aggression, diabetes or other problems. No cases have yet been tried or settled.

The plaintiffs lawyers argue that Pfizer, the world’s largest pharmaceutical company with sales this year of more than $60 billion, neglected to test Chantix adequately before its release, deliberately hid evidence of serious side effects and failed to sufficiently warn consumers about its risks. Pfizer has turned over to plaintiffs lawyers more than six million pages of documents under a protective order that bars their public release.

Pfizer, for its part, defends Chantix and says it “acted responsibly and appropriately at all times in connection with the development, approval, and marketing” of the drug. The FDA, likewise, says it acted properly in approving the drug, despite the problems that emerged after it went on the market.

“The agency does not feel any mistakes were made,” said FDA spokeswoman Sandy Walsh.“We can never speculate as to what may happen with a drug once it goes into widespread use after approval.”

The FDA’s failure at the outset to require Pfizer to include the mentally ill in its research, however, points to a potentially serious flaw in the agency’s regulation of drug safety for these particularly vulnerable consumers. Although the mentally ill commonly are excluded from drug clinical trials, they account for a disproportionate number of smokers and are a key part of the target market for smoking cessation treatments.

Their exclusion baffles experts such as Dr. Karen Lasser, a Boston University researcher who has studied the link between mental illness and smoking. “You need to think about who is going to be taking the drug,” she said.

Paul Thacker, a former Senate Finance Committee investigator who has written about FDA decision-making, agreed. “If you’re not thinking in that way,” he said, “then you’re not doing your job.”

Back when Chantix was approved, Pfizer officials figured they had a potential major new star in their portfolio. With nearly 70 percent of the estimated 45 million smokers in the U.S. hoping to quit, the market appeared to be vast. Sales quickly zoomed to $883 million in 2007, which turned out to be the drug’s peak year. (During the first nine months of this year, sales totaled $522 million.)

Chantix, which is sold as a pill, works by taking the pleasure out of smoking by interfering with the way nicotine ordinarily affects the brain. At the same time, it spurs the release of dopamine, which helps control the brain’s pleasure centers the way smoking usually does.

Pfizer launched Chantix with a news release spotlighting the dire statistics on quitting smoking: less than 7 percent of smokers who try to quit on their own make it past the one-year mark. In contrast, clinical trials showed that about 22 percent of Chantix users who took the drug for three months were able to abstain from smoking for a year or more.

The company early on promoted its product through a series of TV, print and online ads that, without mentioning Chantix or its side effects, sought to sell people on the idea of quitting smoking. The “My Time to Quit” campaign was intended to draw smokers to a website that, after providing quick facts about kicking the habit, tiptoed to information about the drug. Overall, Pfizer has spent about $300 million on advertising for Chantix, according to the Nielsen Co., a media information business.

Pfizer also spread its influence by paying doctors to give talks to other physicians on smoking cessation techniques while also giving funds to universities. The University of Wisconsin-Madison said the company has given it more than $3 million, mainly for continuing medical education courses it offers on smoking cessation.

The multi-pronged promotional effort by Pfizer eventually addressed rising concerns about the drug. In 2008, Joseph Feczko, then Pfizer’s chief medical officer, wrote an opinion piece in the Wall Street Journal. Headlined “Smoking Has Side Effects Too,” the piece tried to offset the negative publicity about Chantix with a reminder on the hazards of smoking. It also explained how regulators and drug companies conduct follow-up research, and alert the public, after they receive reports of serious side effects.

Along the way, a controversial tack Pfizer took to push its product was a study written by a team of employees headed by Kathryn E. Williams, then part of the company’s Global Research and Development unit. The study, which was published in 2007 in the journal Current Medical Research and Opinion, deemed Chantix safe for long-term use. (Labeling on the drug prescribes a 12-week course of treatment, but the study looked at consumers who used Chantix for a year.)

The article, however, was flawed in that failed to provide statistical analysis to back up the claim, according to Dr. John Spangler, a smoking cessation expert at Wake Forest University’s School of Medicine. He wrote to the journal to complain, noting that the numbers actually indicated Chantix patients were 2.5 times more likely to suffer a serious adverse event than those on a placebo.

“I don’t know what they were trying to accomplish,” Spangler said in a recent interview. “A faulty study has been included into the world’s medical literature.” Pfizer declined to comment on the study. The journal, for its part, said via email that the article “underwent rigorous and independent peer review, and full disclosure of the authors’ employment and funding was made.”

Other studies have demonstrated that Chantix has helped some smokers, but often is no better than other options for quitting. For instance, a study published in in the journal “Thorax” in 2008 showed that Chantix works better than the nicotine patch for some people, but not for others. Other researchers have concluded that nicotine gum is just as effective as Chantix.

What’s more, most people who give up smoking quit cold turkey, without medication. A 2006 survey of more than 8,000 smokers by the National Cancer Institute found similar success rates among those who used medication in trying to quit and those who didn’t. The figures showed that 16 percent of the non-medicated group abstained from smoking after nine months, versus 14 percent for the group using medications.

Still, experts such as Lirio Covey, a professor of clinical psychology at Columbia University who worked on early studies of Chantix, say the FDA’s approval of Chantix made sense. “Some people really have a hard time stopping smoking. Chantix does have some utility,” Covey said. “I would say that it’s a pretty good drug, but it’s not the first resort” for treatment.

For Covey, who said she has received close to $80,000 from Pfizer this year to study the effects on mood of smoking cessation, the key facts are these: millions have taken Chantix to stop smoking, and the number of people who suffered severe side effects is relatively small. In her estimation, the benefits of the drug outweigh the risks. She also believes it’s still not clear if the side effects are the result of the drug or nicotine withdrawal.

But questions about why Chantix’s safety wasn’t fully evaluated extend back at least to May, 2006, when the FDA’s safety reviewer for the drug, Dr. Howard Josefberg, submitted his report to the agency. He endorsed approving Chantix, but found that Pfizer’s clinical trials may have been “too carefully screened.” He noted that the studies excluded people treated for depression over the previous 12 months as well as “those with histories of panic disorder, psychosis or bipolar disorder.”

“The patient population studied, then, may not represent the true target population should varenicline be approved,” added Josefberg, using the generic name for Chantix.

The report by Josefberg, who declined to be interviewed for this story, indicated that three or four people died out of the roughly 5,000 smokers treated with Chantix in clinical trials. FDA researchers, however, said all of the fatalities appeared to be unrelated to the drug.

Still, one death in particular piqued the interest of scientists. A white male in his 60s who took the drug for close to six months took his own life. “Patient 103510121069 represents the most potentially concerning case,” Josefberg wrote. He “committed suicide by hanging 27-days after completing the 24-week varenicline treatment.” The patient had a history of severe depression but neglected to share his troubled past with those screening patients, according to FDA documents.

More than 80 other Chantix patients in the trials reported serious side effects. In one case, a 46-year-old white female, who stopped taking the drug after a week, arrived at work speaking incoherently, confronting colleagues, and overturning furniture, according to FDA documents. She was hospitalized for acute psychosis. Later reports indicated the patient had some history of psychotic behavior, but had failed to tell investigators, according to FDA documents.

All told, Josefberg concluded that there was no clear connection between Chantix and any deaths or serious adverse events, psychiatric or otherwise. He recommended the FDA approve the drug with a warning that alerted users to side effects such as potential heart problems, nausea, insomnia and abnormal dreams, while adding that the trial data was far from conclusive on the drug’s cardiovascular effects.

The routine exclusion of mentally ill subjects from clinical trials, researchers say, is justified in certain cases. Sometimes the subjects are too sick to consent to participate. Mentally ill patients may also fail to follow the proper dose regimens or other instructions. In addition, including people with mental or other health problems in drug research can complicate evaluating the results of a medication.

Yet many experts argue that excluding the vast numbers of Americans who are mentally ill from the trials leaves in doubt the real world effects of drugs on many people who may be vulnerable. According to the National Institute of Mental Health, 26 percent of Americans 18 and older, or close to 60 million people, suffer from a diagnosable mental disorder in a given year. About 6 percent suffer from a serious mental illness.

Beyond that, the mentally ill account for a big proportion of American smokers. A report this spring from the U.S. Centers for Disease Control and Prevention found that 43 percent of adults with depression smoke, versus 22 percent of other adults.

Boston University’s Lasser, in a recent analysis relying on the broader definition of mental illness, concluded that people with such disorders represent about 40 percent of all smokers.

Raymond Lorenz, the author of a recent paper on Chantix and the mentally ill and a faculty member at Auburn University’s pharmacy school, said more research is needed to gauge the risks that psychiatric patients face when they take the medication. Still, he wrote that excluding the mentally ill “seems to be a glaring oversight” in Pfizer’s trials before the FDA approved Chantix.

The FDA could have, but didn’t, ask Pfizer to conduct additional research — in this case, research including mentally ill smokers — immediately after Chantix was approved. The agency sometimes does that as a compromise, to ensure that medications reach patients without extra years of delays, while keeping an eye on a drug’s side effects after it comes into widespread use.

By late 2007, however, the parade of Chantix warnings and restrictions by federal authorities had begun. That November the FDA issued a warning that some patients taking Chantix reported having suicidal thoughts. Two months later, the agency ordered revised labeling indicating that Chantix’s safety for mentally ill patients was not established. Other federal agencies also took action, including the Federal Aviation Administration, which banned pilots and air traffic controllers from using Chantix.

Finally, in July, 2009, the FDA came around to fully embracing testing Chantix on the mentally ill. “We are going to require that they study folks that have mental health disorders,” said Dr. Curtis Rosebraugh, an FDA drug evaluation official, in a telephone conference call media briefing. “There is a disproportionate amount [of them] that smoke and they would be potentially exposed to this drug. We have no idea if that subgroup population is at higher risk or not and so we do want to get some sense of that.”

Chantix users like Brandon Campbell already have a sense of that.

In July 2007, Campbell, a 33-year-old IT technician at Duke University Hospital, gave the drug a try after enrolling in an employee wellness program to quit smoking. Although Campbell, like Ware, had a history of depression, there was no indication as yet that the safety of the drug had not been established in people like him. Soon after finishing the recommended 12-week course of treatment, Campbell recalls, he started experiencing severe symptoms. He felt disconnected from reality, had trouble remembering things, and became emotionally unstable—breaking down over trifles. He also contemplated suicide. He’d been depressed before, sure, but had never felt, as he put it, like driving over a cliff.

The problems persisted. This past summer, Campbell said, he sat in his garage in Durham, North Carolina, with the doors shut tight and the car running, hoping to die. Then the police started beating on the door, and he was rushed to the hospital. Campbell still smokes and says he still wants to quit, but he's exceedingly wary of trying any more pharmaceuticals. “It's like playing Russian roulette,” he says.

A new study says a smoking cessation drug manufactured by the pharmaceutical giant Pfizer Inc. is the prescription medication most often linked in the U.S. to violent acts or violent thoughts toward others.

The study, published Wednesday in the journal PLoS ONE , reviewed drugs most often linked to violent thoughts or actual violent acts, such as physical assaults, in reports received by the Food and Drug Administration. It covered a five-year period ending in 2009.

The Pfizer medication Chantix, generically known as varenicline, led the way with 408 reports related to violence.

As FairWarning has reported, Chantix has been associated with serious adverse events, including suicides and attempted suicides and is the subject of about 1,000 lawsuits. But Thomas J. Moore, lead author of the study and a scientist with the the nonprofit Institute for Safe Medication Practicesin Horsham, Pa., argues that more attention needs to be paid to the drug’s potential to induce violence.

Second on the list, after Chantix, was the antidepressant Paroxetine,also known as Aropax, Paxil and Seroxat. It drew 177 reports of violent thoughts or actions.

Among smoking cessation aids, Zyban, also known as bupropion, followed Pfizer, with 35 incidents.

Michael Cummings, a smoking cessation expert at the Roswell Park Cancer Institute in Buffalo, N.Y., who was not involved in the study, questioned the validity of the results. He said the reports reviewed by the researchers are “probably not good enough” by themselves to draw a strong conclusion.

Pfizer, for its part, said “there is no reliable scientific evidence that Chantix causes violent thoughts or actions.”

Among the other drugs associated with violence were medications for attention deficit disorder and sedatives. Moore was joined in the study by researchers from the Harvard University and Wake Forest University medical schools.

In the above article it should be noted that Michael Cummings is paid by Pfizer, Chantix's maker, as a member of Pfizer's Speakers Bureau. If he wants to keep his job what would we expect him to say?

So what's going on here with 9 times as many FDA violence reports for Chantix than NRT? We can only speculate. We know that anger is a normal phase associated with an significant emotional loss, including smoking cessation. We also know that an angry quitter always retains the ability to quickly suppress escalating anger via relapse. Or do they? What happens when Chantix (varenicline) with its 24 hour chemical half-life has bonded with all brain a4b2 type nicotinic receptors, effectively blocking nicotine from attaching and causing significantly greater dopmaine pathway stimulation than afforded by the partial agonist varenicline? For some, can anger escalate into rage? We don't know. It's likely vastly more complex (genetics, mental illness, and including other brain neuro pathways besides dopamine).

The below new Chantix/Champix study review proclaims that the difference in success rates between the NRT and Chantix/Champix at six months is "not statistically significant." If true, with so much concern about serious varenicline adverse events, why isn't this rather important decision making info being widely shared with smokers? I submit that it's the exact same reason that pharm industry financial influence worked so hard in 1999/2000 to get cold turkey (abrupt nicotine cessation) declared non-science-based and black-listed as a government approved quitting method: money/profits.

There is nothing wrong with making money. What's wrong is leading smokers to believe that these products are vastly more effective than they really are. What's wrong is marketing that suggests that few succeed at quitting cold turkey, when each year it generates more successful long-term quitters than all other quitting methods combined, or that these products prevailed over cold turkey quitters when no such trials have ever been conducted, when the industry is afraid to do so, when it knows that doing so would expose and kill its golden "placebo" goose.

Although an extremely limited view that only shows us quitting rates at week 4, the best on-going real-world varenicline data we have to look at comes from the UK NHS Stop Smoking Services, possibly the best/most intense government quitting programs of any nation (except for heavy reliance upon approved quitting products). When reflecting upon the below figures, keep in mind the following factors: (1) that these are 4 week figures, not 6 month rates as discussed in the below study review; and (2) that at 4 weeks, non-medication quitters have already ended dopamine pathway stimulation, re-sensitized receptors and down-regulated the number of receptors to levels seen in non-smokers, while those using "medication" still have 4 to 8 weeks of "treatment" before attempting to adjust to and get comfortable with natural stimulation.

So why does UK NHS limit the data it presents to 4 weeks? We don't know. What we know is that these products were evaluated and approved using 8 to 12 week treatment plans. We also know that the pharmaceutical industry's ties to UK government health officials is likely as great or greater than here in the U.S. Anyway, Stop Smoking Services 4 week quitting method quit rates between 2007 and 2010 were as follows:

So what do long-term (6 months to 1 year) UK NHS Stop Smoking Services quitting rates look like? Well, so far there has only been one study which looked at long-term rates (1 year), the sampling was rather small, and was conducted prior to Chantix / Champix coming on the market. Still, it's the only long-term UK data we have. I prepared the chart to the right from it (link to full text copy of the study - see bottom of Table 6) .

Now, in your mind try to guess where varenicline will fall at 1 year, once users attempt to adjust to its absence and natural stimulation of brain dopamine pathways. Putting it all together, I suspect that varenicline would fall slightly higher than NRT but substantially lower than no medication.

I've shared this info to try and help those just starting out feel a tad more comfortable about your quitting method decision, to help you understand that those claiming that these products double your chances are not being truthful. Yes, inside randomized clinical trials they consistently defeat placebo but placebo isn't a real quitting method. So why do they work inside clinical trials and yet fall flat on their face in real-world use?

The quick answer is that clinical trials were not blind as claimed, that you cannot hide full blown withdrawal from an experienced quitter who is an expert at knowing exactly how it feels. Participants joined the trial seeking 8 to 12 weeks worth of free quitting products that they hoped with diminish withdrawal's intensity. They grew frustrated upon realizing that they had been given an inert placebo instead. We know from the few blinding integrity assessments that have been published that 3 to 4 times as many placebo group members correctly identify their assignment to placebo as guess wrong. If you'd made the same realization, would you have stuck around and allowed researchers to toy with you for weeks or months? Many of them didn't either.

So, if just starting out and worrying that maybe you've taken the less successful road, rest assured that you've made an excellent selection! In fact, cold turkey provides 100% odds of success so long as all nicotine remains on the outside. Yes, there was always only one rule ... no nicotine today!

Breathe deep, hug hard, live long,

John (Gold x11)

Varenicline Increases Smoking Abstinence at 6 Months to a Year Compared With Placebo or Bupropion; Nausea Is the Most Commonly Reported Adverse Effect

Context

Cigarette smoking is the leading cause of preventable premature death in the world, with an estimated 5 million smoking-related deaths worldwide. Quitting substantially reduces the health risk associated with smoking. Treatments available for smoking cessation include nicotine replacement therapies (NRTs), bupropion and the most recently marketed, varenicline. Varenicline, an analogue of cytisine, is a partial agonist for the α4β2 subtype of nicotinic cholinergic receptors, which are associated with the addictive effects of nicotine. Varenicline may help smokers quit smoking by reducing the rewarding effects of nicotine as well as attenuating the withdrawal symptoms.1 This meta-analysis evaluated the efficacy and safety of partial nicotine agonists, varenicline or cytisine, compared with placebo or other treatments in clinical trials conducted worldwide.

Methods

Cahill and colleagues conducted a Cochrane review evaluating the efficacy of partial nicotine agonists, varenicline or cytisine, for smoking cessation. Randomised controlled trials comparing active drug with placebo were included in the analyses. The review also included studies comparing the efficacy of varenicline with bupropion or NRT. Studies were excluded if they did not have a minimum of 6-month follow-up data from the beginning of treatment. Literature searches were conducted using the Cochrane trial register and other databases including MEDLINE, up to September 2010. The main outcome was the smoking abstinence rate at 6 months or more. Biochemical measures of smoking abstinence were the preferred outcome. One author extracted the data, and another author checked them. The authors used a meta-analysis to produce a RR, using the Mantel–Haenszel fixed-effect model. The heterogeneity of the studies and publication bias were also assessed.

Findings

A total of 16 studies were included in the analyses, 15 for varenicline and 1 for cytisine. Twenty-one studies were excluded. The main finding of the review was that the usual recommended dose of varenicline, 1 mg twice daily, was more effective than placebo for continuous abstinence at 6 months or longer (RR 2.31, 95% CI 2.01 to 2.66). Lower or variable doses of varenicline were also more effective than placebo (RR 2.09, 95% CI 1.56 to 2.78). Results also indicated that varenicline was more effective than bupropion at 1 year after the initiation of treatment (RR 1.52, 95% CI 1.22 to 1.88). Similarly, varenicline was more effective than NRT at 24 weeks, although this effect was not statistically significant (RR 1.13, 95% CI 0.94 to 1.35). Overall, varenicline was well tolerated even beyond the 12-week recommended treatment period. Nausea was the most common side effect, with a dose-dependent effect. The results did not show the behavioural adverse events reported in the postmarketing stage including depressed mood, agitation and suicidal behaviour or ideation. The single trial of cytisine was inconclusive.

Commentary

The results demonstrate the efficacy of varenicline, relative to placebo, as a pharmacological treatment for smoking cessation in the usual recommended dose as well as at lower or flexible-dosing schedules. The results also suggest that varenicline may be more effective than bupropion. However, this comparison of efficacy was based on only a few studies. Future studies specifically designed to compare the efficacy of NRTs, bupropion and varenicline are needed.

What remains to be determined is whether varenicline will have similar efficacy in samples representative of all smokers. The clinical trials included in the meta-analyses excluded smokers with medical or psychiatric comorbidity or with other addictions. It has been estimated that at least one-third of smokers in the USA have a psychiatric disorder or another addiction.2 Thus, it will be important to conduct studies including these subject populations as well. Indeed, the authors identified numerous ongoing trials in these areas. In addition, clinical trials generally provide more psychosocial treatment than those provided in clinical settings. It will also be important to show the efficacy of varenicline in real-world settings.

This meta-analysis supports the safety of varenicline up to 1-year duration. These findings do not support the postmarketing reports of depressed mood, agitation and suicidal behaviour or ideation associated with varenicline treatment. However, due to the selection biases of the included studies, the absence of these putative severe adverse events in this review is by no means dispositive. The causal relationship of these side effects to varenicline treatment or smoking cessation effect remains to be determined.

Footnotes

Competing interests MEM has received unrestricted research grants, including salary support, from Pfizer. MS and DD have no conflicting interests.

While reported serious psychiatric side effects of varenicline prompted the FDA to require a boxed warning and mandatory Medication Guide for patients in 2009, we discovered the FDA had been unaware of hundreds of serious psychiatric adverse event reports that were originated by Pfizer and dated back as far as 2006. These reports had not been promptly submitted into the agency's AERS safety database as the FDA had expected. Thus, FDA analysts could not evaluate 150 completed suicides reported to the company, along with hundreds of other cases indicating psychosis, depression, or attempted suicide. We explain this significant breakdown in safety surveillance below, and recommend the FDA investigate why Pfizer was reporting suicide deaths as "expected adverse events."

Varenicline, an aid to smoking cessation, was approved in 2006, and by 2008 was being taken by hundreds of thousands of smokers who wanted to quit. But as patient exposure increased, the FDA adverse event reporting system received hundreds of reports of psychiatric side effects and other potential safety problems. When we first examined quarterly data for varenicline in May 2008, adverse event reports for the drug outnumbered those for other prescription drugs on the U.S. market including inherently toxic cancer chemotherapy agents, high-alert drugs that suppress the immune system, and extremely potent synthetic opioids. [21] Pfizer told the FDA that it thought stronger warnings were not necessary, and said “it was not unexpected” to see psychiatric side effects among smokers, and in particular those who might be experiencing nicotine withdrawal. [22] The FDA disagreed after completing its own analysis of the adverse event data [23] [24] and in July 2009 required strong warnings for both doctors and patients. [25] Even these warnings, we have now learned, were based on significantly incomplete data about psychiatric side effects.

Results for Third Quarter 2010

We began a new investigation into a signal for varenicline after observing the drug was again setting records. After peaking in 2008, both dispensed prescriptions and reports of serious injury then declined modestly. With a new spike totaling 1055 serious adverse drug events meeting QuarterWatch criteria for the third quarter of 2010, it again surpassed all other drugs we regularly monitor (Excludes 226 cases linked to legal claims. See Table 4.) It also ranked first in reported deaths, more than twice as many as any other drug we regularly monitor. Varenicline cases also outnumbered all regularly monitored drugs for specific conditions as measured by Standardized MedDRA Queries (SMQs). It accounted for more possible cases than any other drug for suicidal/self-injurious behavior, depression, psychosis, hostility/aggression, and convulsions.

Further analysis uncovered the reason for the sudden spike in varenicline reports. The third quarter totals for 2010 had been boosted by 589 reports about serious and fatal adverse events that had occurred in prior years but were not entered into the FDA AERS monitoring system until July 2010. We found 12 newly entered cases with manufacturer dates from 2006, the year varenicline was first approved, 119 from 2007, and 176 additional cases from 2008. The rest of the 589 cases were for 2009 and early 2010, but also not entered into the reporting system until July 2010 or later.

150 Completed Suicides

Prominent among these newly available cases were 150 completed suicides identifying varenicline as the primary suspect drug. These additional cases more than doubled the total suicides that were in the AERS system and available to the FDA and others for safety analysis. Here is our breakdown:

Prior to July 2010 the AERS system had 37 completed suicide cases submitted by the manufacturer identifying varenicline as primary suspect drug.

Another 85 suicides associated with varenicline were reported directly to the FDA by health professionals or consumers, and entered into the system without manufacturer involvement.

In July 2010, these additional 150 suicide cases from the manufacturer first become available.

The newly available completed suicides were not the only reporting and coding problems we detected. These suicides numbered among the 589 cases that met the regular QuarterWatch criteria. This group also included 102 possible cases of hostility/aggression, 156 cases of depression, and 56 cases of possible psychosis. (A case could be classified into more than one of these categories.) In addition, the manufacturer submitted in July 2010 more than 26,000 additional varenicline adverse event cases that did not meet the standing QuarterWatch criteria for serious, domestic adverse events. While we have not fully analyzed this larger group of 26,000 cases, a preliminary survey indicates this group includes numerous additional cases of psychiatric side effects that affect the safety profile of varenicline. Having discovered this large body of significant new safety information submitted in July 2010, we sought to learn how this had occurred.

Comments Sought

We communicated our preliminary findings to the manufacturer, Pfizer, and sought an explanation of these delayed case reports. As has been the case since 2008, Pfizer declined to respond to our questions about varenicline or any other of its products. In a minor policy change, Pfizer said that this time, it could not respond because QuarterWatch data or one of the QuarterWatch project team members might be involved in the future in legal cases involving the safety of varenicline. Previously Pfizer had not indicated why it chose not to respond to ISMP's offer to discuss its findings in advance.

In addition, we communicated our preliminary findings to the FDA. The agency provided a useful and detailed response that resolved some of our questions, but left others unanswered. Based on the information available, a review of the FDA's adverse event reporting regulation and other industry guidance, here is our understanding of what went wrong.

What Went Wrong

Since 1998 the FDA's primary tool for postmarket safety surveillance has been its computer database called the Adverse Event Reporting System (AERS) into which hundreds of thousands of case reports flow each year. Safety analysts at the FDA search this data base routinely to identify reports that might signal a safety issue for additional study. For new, serious adverse events (called expedited reports) the manufacturer is required to report within 15 days, and today most submissions are electronic and flow automatically into the agency safety database. For the less important non-serious events and a few serious adverse effects that are well-characterized, the updates take place on a quarterly basis and are called Periodic Reports. However, the 26,000 cases described above had not been previously submitted to this key safety data system as the FDA expected.

In addition, the FDA requires manufacturers to submit a text report and analysis on a quarterly basis for the less important periodic cases. Listings of the 26,000 case reports were included in these quarterly text documents, the FDA said. Until 2010, the FDA said, it had not been fully aware that some manufacturers were not submitting the case reports into both systems. The agency also said the problem was not limited to varenicline or to Pfizer alone.

Unanswered Questions

We still do not understand why Pfizer grouped hundreds of cases of suicide, suicide attempt, and psychosis among more than 26,000 mostly non-serious adverse events submitted in an inaccessible text report format—especially prior to July 2009 while these safety issues were being actively evaluated by the FDA. To classify a suicide or suicide attempt as an “expected adverse event” rather than submitting it promptly as a 15-day report where it would have been immediately available is troubling in our view. Additional questions arise about how Pfizer coded hundreds of reports of depression and suicidal ideation. When the FDA surveillance system did not include more than half the reported suicide deaths in which varenicline was primary suspect drug, it is a safety lapse that warrants careful investigation.

FDA Warning Letter Sent

In addition, the agency has raised other concerns found in an inspection of Pfizer’s adverse event reporting program. The FDA’s Inspections, Compliance, Enforcement and Criminal Investigations unit sent Pfizer a six-page warning letter on May 26, 2010 indicating the agency had found deficiencies in the company’s adverse event reporting program dating back to 2004. [26] Among the violations the FDA alleged had occurred were failure to submit serious adverse event reports for cases already in company files until identified by an inspector, misclassifying and downgrading events without reasonable justification, and failing to submit expedited reports within 15 days as required. The agency also alleged Pfizer had failed to keep prior commitments to improve training and performance for adverse event reporting. The specific cases cited as examples in the letter did not include varenicline but applied broadly to Pfizer’s safety surveillance program.

Hundreds of reports of suicides, psychotic reactions and other serious problems tied to the popular stop-smoking drug Chantix were left out of a crucial government safety review because Pfizer Inc., the drug's manufacturer, submitted years of data through "improper channels."

Some 150 suicides — more than doubling those previously known — were among 589 delayed reports of severe issues turned up in a new analysis by the non-profit Institute for Safe Medication Practices.

"We've had a major breakdown in safety surveillance," said Thomas J. Moore, the ISMP senior scientist who analyzed the data. The serious problems — including reports of completed suicides, suicide attempts, aggression and hostility and depression — had been mixed among some 26,000 records of non-serious side effects such as nausea and rashes, with some dating back to 2006, the year Chantix, or varenicline, was approved.

They echo previous claims that the drug can induce extreme reactions in people trying to quit cigarettes, including vivid nightmares, crippling depression and sudden, violent outbursts.

"It's really chilling," said Moore, who analyzed 26 Chantix reactions in a paper published in the September 2010 issue of the Journal of Pharmacotherapy. "This seems to unleash something in people. It can be violence to anything around."

Moore's case studies describe "inexplicable and unprovoked" reactions in Chantix patients with no previous history of violence or mental illness, including:

A 24-year-old woman who started beating her boyfriend in bed because "he looked so peaceful" and later attempted suicide;

A 42-year-old man who punched a stranger at a bowling alley;

A 47-year-old woman who died after she came out of a room, yelled at her daughters and then shot herself.

Federal Food and Drug Administration officials acknowledged that they asked Pfizer to resubmit thousands of records after realizing that the company was sending required reports in an inappropriate format that could not be added to the agency's Adverse Events Reporting System, or AERS.

"Last year, FDA became aware that a few manufacturers were submitting adverse events reports to FDA through improper channels," the agency said in a statement.

Pfizer officials said they were submitting reports as required and that when the FDA asked them to change, they did so immediately. They said there's no proof that Chantix causes suicide or other serious side effects.

Moore, who has served as an expert witness in court regarding Chantix, said it's the riskiest drug among those analyzed from the FDA's adverse event reports. In the third quarter of 2010, it ranked first in reported deaths, with twice as many fatalities logged as any other drug, he said.

New reports don't change FDA's position.

FDA officials said the new reports did not change the agency's position on the risks and benefits of the controversial drug, which received a black box warning that included suicide — the strongest caution possible — in 2009, according to agency officials who would not speak on the record.

"At this point, based on the data, FDA does not have any new safety concerns with Chantix, though those that have been established remain under active review,” the agency said in a statement posted in response to the ISMP report.

Agency officials said they're continuing to review Chantix in clinical trials and two large observational studies with the Veterans Administration and the Department of Defense.

But Moore said the new data should raise immediate alarms about the drug that was prescribed 3.2 million times last year to people trying to stop smoking — and 1.1 million times already this year, according to data from the firm Wolters Kluwer Pharma Solutions.

"To us, it raises questions about whether this drug is safe for widespread clinical use," Moore said. "Does this tip the balance?"

That's a view echoed by families of people who allegedly became suddenly and inexplicably violent after taking Chantix. Sean M. Wain, 34, of Beaver County, Pa., shot himself and his wife, Natalie, 33, in May 2009 in what a lawyer for their families claims was a Chantix-fueled rage.

If the FDA had more information about suicides and other side effects tied to Chantix, the agency might have taken stronger action sooner, said Victor H. Prebanic, who represents Robert Erdelen and George Wain, fathers of the slain couple.

"If Pfizer had been more forthcoming, the black box warning might have emerged earlier," Prebanic said. "For all we know, the drug would not have been available."

The lawsuit, filed this month, is the latest among hundreds of claims filed against Pfizer regarding Chantix. At least 1,545 injury claims that cite Chantix are pending in federal court.

Pfizer officials, however, said that the firm was following the FDA's rules and changed their reporting process once the agency asked for clarification.

"All post-marketing reports of adverse events are reviewed by Pfizer and reported to regulators, including FDA, in accordance with regulatory guidelines," the company said in a statement. "Pfizer takes patient safety and regulatory reporting obligations very seriously."

Suicide is an 'expected' event?

The problem appears to have been caused in part by federal Food and Drug Administration rules that don’t require firms to submit new reports of death or serious harm in the agency's system for urgent review when such risks are already known.

FDA requires drugmakers to submit adverse events in two ways: There's an "expedited" system that requires companies to report serious and unexpected adverse events into the AERS system within 15 days.

Companies are also required to submit less-serious and expected adverse events quarterly in so-called "periodic reports." In those cases, problems previously included on drug labels — including suicide and suicide attempts — are considered to be expected events.

In Pfizer's case, the firm was submitting the periodic reports as required, but combining summaries and individual case reports in a single text file, the FDA said.

That meant that the individual reports of injury were not logged in the FDA's AERS system, drastically reducing known reports of suicides and other psychiatric problems tied to Chantix, Moore said.

"It's very clear the suicide risk of this drug was higher than we knew," he said.

Overall, there were 1,055 reports of serious problems with Chantix reported in the third quarter of 2010, more than any other prescription medication regularly monitored by the drug safety agency, Moore said.

Before last July, the FDA had logged 122 reports of suicides linked to Chantix, including 37 reported by Pfizer and 85 reported by health professionals or consumers, Moore reported. After the 150 new Pfizer reports were added, the total jumped to 272.

In addition, the 589 new reports of severe problems included 102 cases of possible hostility and aggression, 156 cases of depression and 56 cases of possible psychosis. Those were mixed among the 26,000 reports of less-serious problems.

Moore has asked the FDA to investigate the 150 new suicide reports, particularly if the events occurred before the 2009 black box warning listed suicide as a possible side effect.

For their part, FDA officials said they are considering changing regulations to allow expedited reports of suicides and other serious problems, even if they've previously been identified as expected. First proposed in 2003, that change is still pending.

Varenicline Cardiovascular Risk?

Thanks to all who wrote making me aware of the Canadian Medical Association Journal (CMAJ) study suggesting existence of varenicline (Champix / Chantix) cardiovascular risks, especially Kathleen Craig. A free full-text PDF copy of the study entitled "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis" by Sonal Singh and others can be found at this CMAJ link. But before spending time reading it you need to be aware tht the magnitude of any cardiovascular risks associated with varenicline use is being challenged via CMAJ online "Responses" suggesting that the authors have significantly overestimated risk of serious cardiovascular events if they used the figures presented in their paper.

Regardless of the outcome of the debate over the actual odds of cardiovascular risk, I submitted my own CMAJ response (below), pointing out how, to this day, physicians are unable to engage in meaningful varenicline risk benefit analysis or adequately advise patients, because as of yet there have been no studies evaluating varenciline's worth as a stand-alone aid, unaccompanied by counseling or support, the manner used by most quitters.

In my mind, it makes no sense to toy with risk of serious injury or death without any idea as to the likelihood of long-term success after doing so.

In looking at my below comments please, be sure to note my Conflict of Interest disclosure statement at the bottom. Still just one guiding principle making sure that quitting method concerns never again need be our concern .... no nicotine just one day at a time, Never Take Another Puff, Dip or Chew!

Breathe deep, hug hard, live long,

John - Gold x12

Varenicline's missing risk-benefit analysis

While Singh and colleagues add risk of serious adverse cardiovascular events to an already frightening drug risk profile, how can physicians engage in meaningful risk-benefit analysis when varenicline has yet to be studied as a stand-alone quitting aid, unaccompanied by formal counseling and support? According to the June 2000 U.S. Clinical Practice Guideline, the number of clinical trial counseling/support contacts and total contact time could account for nearly all successful cessation

While Singh and colleagues add risk of serious adverse cardiovascular events to an already frightening drug risk profile, how can physicians engage in meaningful risk-benefit analysis when varenicline has yet to be studied as a stand-alone quitting aid, unaccompanied by formal counseling and support? According to the June 2000 U.S. Clinical Practice Guideline, the number of clinical trial counseling/support contacts and total contact time could account for nearly all successful cessation among varenicline users in all trials to date.[1]

The just released Hughes varenicline study is the closest yet to replicating real-world conditions.[2] There, success rates declined to just 14 percent at 24 weeks among a population of moderately motivated smokers who wanted to quit, but when asked, had no plans within the next 30 days. That's roughly a 200 percent decline over six-month varenicline rates seen in Pfizer's phase III FDA drug approval studies.[3]

Those 2006 studies provided participants up to nineteen counseling/support sessions by week 24.[3] In contrast, the Hughes et al study provided only eight: four counseling sessions and four follow-up data seeking telephone calls.[2] But still, varenicline is vastly superior to products already on the market, correct?

The Aubin 2008 Thorax study found that when analyzed using 7-day point prevalence rates, varenicline failed to show statistically significant benefit over nicotine patch, reporting "no significant differences at week 24 ... or at week 52," despite varenicline having been used two weeks longer than the patch.[4]

Here in the U.S., according to the latest report of Food & Drug Administration (FDA) adverse event watchdog Institute for Safe Medication Practices (ISMP), varenicline ranks first in reported deaths, more than twice as many as any other drug regularly monitored.[5] According to the report, there were "1055 serious adverse drug events meeting QuarterWatch criteria for the third quarter of 2010," and varenicline accounted for "more possible cases than any other drug for suicidal/self-injurious behavior, depression, psychosis, hostility/aggression, and convulsions."[5]

An email yesterday from ISMP's senior scientist states that the total number of U.S. varenicline adverse event cases reported to the FDA through the 3rd quarter of 2010 stands at 36,342, including "272 cases of completed suicide, 323 cases of suicide attempt and 63 cases described as suicidal behavior."[6]

What percentage of Canadian varenicline users use it in a stand-alone manner? I submit that far more are doing so than not. If so, prior to a decision accepting varenicline's risks, should patients be told varenicline's long-term cessation rate when unaccompanied by counseling or support? In that varenicline's stand-alone worth is still unknown, how can patient informed consent, as yet, be meaningful?

[6] Thomas J. Moore, a July 6, 2011 email from tmoore@ismp.org signed by Thomas J. Moore, Senior Scientist, Institute for Safe Medication Practices to John R. Polito sharing varenicline data from the QuarterWatch data base, a master file of all cases reported to the U.S. Food and Drug Administration, July 06, 2011.

Conflict of Interest:

I am an advocate of abrupt nicotine cessation (cold turkey), the method that each year produces more successful Canadian ex-smokers than all other methods combined.

So why does varenicline (Chantix / Champix) routinely prevail over placebo inside clinical trials in which smokers seek out study participation, yet below fail to prevail over placebo among a somewhat captive population of hospitalized smokers/quitters? Could it be that particpant medication expectations are significantly diminished when hospitalized? Hopefully this study has researchers reflecting upon natural study biases introduced through study marketing and disclosures during informed consent. With researchers needing to disclose so many Chantix/Champix potential adverse event risks, just maybe after hearing them the hospitalized particpant was just as happy to be assigned to receive an inert sugar placabo pill instead.

Abstract

OBJECTIVE:

The hospital can be an important opportunity for smoking cessation interventions. This is the first randomized, double-blinded, placebo-controlled pilot trial utilizing varenicline and post-discharge, in-person behavioral treatment for hospitalized smokers.

METHOD:

Seventy-nine smokers admitted to a university-based hospital with various diagnoses were enrolled from 2007 to 2009. The primary outcome was biochemically confirmed abstinence at 24weeks following discharge. Secondary outcomes included withdrawal symptoms, motivation, utilization of treatment, and medical events.

RESULTS:

Overall abstinence at 24weeks was 27% with no difference between vareniclineand placebo treatment groups (23% vs. 31%). There were no significant differences in motivation to stop smoking or withdrawal symptoms. Over 40% of all subjects utilized post-discharge behavioral treatment with significantly higher abstinence rates compared with those who did not (53.1% vs. 8.5%, p<0.01). Overall adverse events were similar in both treatment groups with the only significant difference being more nausea in the varenicline group (25% vs. 5%; p<0.01). Twenty-three subjects were re-hospitalized with no significant differences between treatment groups (13 varenicline vs. 10 placebo).

CONCLUSION:

This pilot trial of varenicline in hospitalized smokers demonstrated feasibility of implementation, produced some hypothesis-generating findings, and suggested the potential benefit of face-to-face treatment following discharge.

The Wrong Way to Quit Smoking

By Neil Wagner

A new study published in PLoS One found that 90 percent of the reported suicides of people taking anti-smoking drugs over the past 13 years involved the drug Chantix (varenicline)

It's not easy to quit smoking, and many who try turn to anti-smoking drugs for help. But some medications can do more harm than good.

Consider the drug Chantix (varenicline), marketed by Pfizer. Of the reported suicides of people taking anti-smoking drugs from 1998 through September 2010, more than 90 percent were taking varenicline. And the drug was on the market for only four of those years. Add in other safety concerns about varenicline, and you're left with an extremely poor choice for people who want to quit smoking.

That's the conclusion of a recently published study that looked at reports of adverse events since 1998 for the three major types of smoking cessation drugs: varenicline, the antidepressant bupropion, and nicotine replacement products such as gum and patches.

Varenicline and bupropion already carry a black box warning to doctors about possible suicide and depression. But there's been little information about how often each drug causes these side effects or comparisons between them of how frequently they do so. This study found that varenicline did so much more frequently than bupropion.

Varenicline has also been linked to aggression and violence in three studies and carries a warning about this. Its effects on vision, cognition, and motor control have led to its being banned for airline pilots, air traffic controllers, military pilots, and missile crews, and restricted for truck drivers.

Quitting smoking brings undeniable health benefits, but the risks associated with this drug suggest that other methods should be tried first. In the study authors' own words, Chantix or varenicline is "unsuitable for first-line use in smoking cessation."

Often, serious side effects of a drug don't become apparent until years after the drug is first marketed. The place they tend to show up first is the FDA's Adverse Event Reporting System (AERS).

In the current study, the researchers found 3,249 AERS reports of serious injurious behavior or depression from people taking the three types of smoking cessation drugs from 1998-2010. Fully 2,925 of these came from people taking varenicline (90 percent), compared to 229 for bupropion (seven percent) and 95 for nicotine replacement products (three percent). There were 295 successful suicides; 272 of these were in varenicline users (92 percent), 19 in bupoprion users (six percent) and four in nicotine replacement drug users (one percent). Results were similar for attempted suicide.

Using a statistical method called disproportionality analysis, the researchers calculated that varenicline was 8.4 times as likely as nicotine replacement products and 2.9 times as likely as bupropion to lead to suicidal behavior or depression.

Disproportionality analysis isn't powerful enough to give a reliable estimate of how frequently a drug causes a particular side effect like suicidal behavior or depression from this small number of cases. But it is an accepted way of measuring whether a drug is causing a higher than normal amount of a particular side effect and of comparing the ability of two different drugs to cause a side effect. Here, it's showing that varenicline seems by far to be the most dangerous of the three anti-smoking treatments.

The researchers speculate that the actual incidence of depression or suicidal behavior from varenicline could be anywhere from around a tenth of a percent to over one percent. It would take information from a much larger number of users to fine tune this estimate.

The study seems to contradict a recent review by the FDA that found no difference in psychiatric hospitalizations between varenicline and nicotine replacement patches. But the study authors explain that this is probably because suicide, depression, and other serious psychiatric side effects often don't result in hospitalization.

For people who are taking varenicline, some signs that it's affecting your behavior are thoughts about suicide or dying, new or worse depression, anxiety, panic attacks, feeling very agitated or restless, acting aggressively, or being angry or violent. A more complete list can be found in the Chantix Medication Guide.

We now have two clinical trial efficacy findings and the following population level effectiveness finding documenting that varenicline is no more effective than NRT, when all population level findings since 2000 indicate that long-term NRT use is no more effective than quitting without it. So the question becomes, why is this important decision making information not being shared with smokers when varenicline use risk concerns are so great?

Source: Division of General Medicine, Baystate Medical Center, Springfield, MA, United States; Tufts University School of Medicine, Boston, MA, United States.

Abstract

BACKGROUND:

Smoking is a major cause of morbidity in lower socioeconomic groups. In randomized trials, varenicline improves long term quit rates, but effectiveness in a clinic setting is unknown.

METHODS:

We conducted a retrospective cohort study of adults who received a prescription for varenicline or nicotine replacement therapy (NRT) at two inner city health centers in 2008-9. Primary outcome was smoking status at 52weeks. Secondary outcomes included follow up visits, behavioral counseling, and side effects. Multivariable Poisson regression was used to compare quit rates with varenicline and NRT adjusted for covariates.

KEY RESULTS:

A total of 371 patients received a prescription for varenicline (46%) or NRT (54%). The mean age was 43years, 58% were female, 44% white, 29% African American and 12% Hispanic. Mental illness, alcohol and drug abuse were common. Within one year, 247 (67%) had follow-up, and 26 (10.5%) maintained abstinence through week 52, 10.2% with varenicline and 10.8% with NRT (p=1.0). Loss to follow-up was 37% for varenicline, 31% for NRT (p=0.20). Including lost patients as smokers, the adjusted quit rates for varenicline and NRT were similar (6.5% vs. 7.6%, p=0.69). Only 69/371 (19%) received behavioral counseling. Counseled patients were more likely to maintain abstinence (13% vs. 7.8%, p=0.04). Side effects were more common with varenicline than NRT (6.5% vs. 2.5%, p=0.07).

CONCLUSION:

In an inner city clinic, abstinence rates were lower than those in clinical trials and did not differ between varenicline and NRT.